Preliminary Clinical Research

Abstracts Presented at the European Society of Aneasthesiology and Intensive Care Medicine- Euroanaesthesia Congress (December 2021)

e poster abstract 6657 adiposity.pptx

e poster abstract 6746 Correlationa.pptx

ABSTRACT 6657

The role of adipose tissue in the metabolic regulation of the stress response to surgery

Tupper-Carey D. Biswas S. Lee B. Dhillon M. Tun H. O. Mcgraw P. Clinical Research Unit, Ng Teng Fong General Hospital and Singapore Immunology Network, Agency for Science Technology and Research, Singapore.Immunology Network, Agency for Science Technology and Research, Singap

Introduction & Study Aims

The stress response to surgery is a highly regulated host survival response that integrates nervous system, endocrine, metabolic, and immune mechanisms to coordinate tissue healing following injury. Metabolic components of the stress response to surgery provide the host with fuel substrates to generate an acute inflammatory response through the rapid activation of the innate immune system. These metabolic substrates include both glucose and free fatty acids for leucocytes.

Adipose tissue functions both as a metabolic fuel store and as an endocrine organ secreting adipokines that regulate metabolism depending on host nutritional availability. A potential role for adipose tissue in acute life threatening tissue injuries has been highlighted by studies linking body adiposity with survival following major surgical procedures; this is referred to as the obesity paradox.

The aim of this exploratory observational study was to investigate the relationship between indices of body adiposity and plasma metabolic mediator concentation profiles during the stress response to surgery .

Methods & Measurements-

A total of 26 subjects were enrolled from patients undergoing unilateral total knee arthroplasty surgery. A baseline metabolic screening assessment was performed for all subjects (Table 1) which included BMI and semi-quantitative measurements of visceral adipose tissue using DEXA scanning (DEXA VAT).

Plasma stress response mediators were measured at baseline (A), 24 (B) and 72 (C) hours following surgery. A panel of mediators was measured using bead based multiplex assays (See Abstract.6746).

Correlations were measured between indices of body adiposity and plasma metabolic and immune mediator concentrations using Spearman rank correlation coefficients. Adjusted p values were performed for multiple testing corrections.

Results-

Baseline characteristics of subjects are shown in table 1 reflecting a typical cohort of patients undergoing total knee arthroplasty surgery.

Table 1. Adiposity Abstract

A high proportion of subjects met criteria for the metabolic syndrome (Asian criteria). Correlations between indices of adiposity (BMI and DEXA VAT) are shown in Table 2. In this group of subjects. leptin (A & C) concentrations show a stronger correlation with BMI compared to VAT, whereas insulin (A) and visfatin/NAMPT (B) show stronger correlations with DEXA VAT compared to BMI,

Table 2 Adiposity Abstract

Fig 1. Scatter Plot DEXA VAT v Vifatin/NAMPT (B)

Fig 1 Scatter plot of Visfatin/NAMPT [B} v DEXA VAT (rho=0.661 p=0.0003, adj p=0.03)

Discussion & Conclusions-

The above correlations observed between indices of adiposity and metabolic stress response mediators reveal that leptin, insulin, and visfatin/NAMPT show significant associations with adipose tissue deposition. Both fasting plasma leptin and insulin concentrations are known to be correlated with indices of body adiposity under resting conditions.

The finding of a statistically significant correlation between visfatin/NAMPT and semi-quantitative measures of visceral adipose tissue deposition is notable because firstly it of similar magnitude to insulin and secondly this correlation was observed at 24 hours following surgery.

Gene expression studies combined with quantitative measurements of visceral adipose tissue deposition have previously been performed to investigate the source of visfatin/NAMPT in the blood. Whilst gene expression studies have demonstrated that visceral adipose tissue is a potential source of visfatin/NAMPT, correlations observed between quantitative measurements of visceral adipose tissue and plasma concentrations of this adipokine are low. However, these studies have been performed under resting conditions; by contrast this study measured both resting and stressed conditions. The strongest correlation was observed under peak stress conditions at 24 hours post major surgery. This preliminary study supports further research to investigate the adipokine visfatin/NAMPT as a specific metabolic stress response mediator secreted in part by visceral adipose tissue into the bloodstream in response to serious tissue injury.

ABSTRACT 6746

Correlations between the concentration profiles of metabolic mediators during the stress response to major surgery.

Introduction and Study Aims

The stress response to surgery involves the simultaneous activation of multiple endocrine cell signalling pathways within the body. These pathways are highly regulated to produce a coordinated response involving multiple physiological systems. The stress response to surgery is an energy dependent process and metabolic components of the stress response provide the necessary fuels for leucocytes involved in this inflammatory response.

This exploratory observational study aimed to investigate correlations between metabolic and endocrine mediators to search for potential underlying regulatory mechanisms during of the stress response to surgery,

Methods and Measurements-

26 subjects were recruited undergoing elective unilateral total knee arthroplasty surgery as described in abstract 6657 above which included a metabolic screen. A panel of plasma metabolic stress response mediators was measured at baseline (A), 24 (B) and 72 (C) hours during the perioperative period of surgery as shown in Slide 1 (slideshow 1) Changes in these mediator concentrations between time points A to B and between B to C were calculated as depicted in Slide 2 (slideshow 1) to estimate the hyper and hypo-inflammatory phases of the stress response. In additon the change concentration over the 72 hour period was also calculated for each mediator (C-A).

Slideshow 1

Slideshow 1-

Slide 1 study stress response mediators measured at time points A,B & C. during the perioperative period.

Slide 2 study stress response mediator concentration changes measured during the perioperative period (B-A, C-B and C-A)

Relationships between mediator concentration changes were investigated to search for potential patterns in mediator release during the stress response to surgery. Patterns of mediator activation were explored by investigating correlations between the hyper- and hypo- inflammatory phases for each mediator (B-A v C-B) as well as to search for correlations between diferent mediators during the study period (p values were adjusted for multiple testing- p-adj).

Results

Mediators with the strongest correlations between the above concentration changes are shown in Table 1 section 1. Line graphs these mediators depicting the concentrations time curve for each subject are shown in slideshow 2. Scatter plots of these concentration changes depicting changes during the hyper- and hypo-inflammatory phases of the stress response are also shown in slideshow 2. The mediators insulin (slides 1 & 2), the incretin GIP (Slides 3 & 4), leptin (Slides 5 & 6) and C-peptide (slides 7 & 8) showed strong inverse correlations between changes in concentration during the hyper and hypo-inflammatory phases of the stress resposne to surgery.

Copy of Untitled spreadsheet

Table 1

Correlation coefficients for study stress response mediator concentration changes. (Spearman Rank Correlation Coefficient (Rho), P and adjusted p values (p_adj) for multiple comparisons

Slide show 2

Slideshow 2 Slides 1-16

Correlations were then explored between mediators (Table 1 Sections 2-4)) . Strong correlations were observed between changes in insulin and GIP concentrations and between C-peptide and GIP during these two phases of the stress response to surgery (slideshow 2). In addition, a strong correlations was observed between absolute concentrations of insulin and visfatin/NAMPT at time point B slideshow 2, slide 10) which is at the peak of the stress response.

Conclusions-

The rapid activation of the innate immune system in resposne to tissue injury requires glucose as the substrate for aerobic glycolysis (the Warburg effect). The combined effects of increased insulin resistance and increased insulin secretion boost leucocyte glucose flux during inflammation.

These correlations highlight potential metabolic stress regulatory mechanisms controlling insulin secretion following surgery. These mechanisms include both the adipokine visfatin/NAMPT and the incretin GIP. These findings are relevant to surgery as well as to metaboic diseases.

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